Activity-dependent processes that persistently modify the strength of synaptic transmission are thought to have a crucial role in the formation of new memories during learning. In the hippocampus, a region of the brain known to have an important role in memory formation, excitatory synapses are capable of undergoing both long-term potentiation (LTP), a long-lasting increase in synaptic strength, as well as long-term depression (LTD), a persistent decrease in the strength of synaptic transmission. Although induced by very different patterns of synaptic activity, the induction of both LTP and LTD is dependent on activation of NMDA-type glutamate receptors. Importantly, NMDA receptors and many of the intracellular signaling pathways involved in plasticity are organized into multi-protein complexes by a family of scaffolding or adaptor proteins known as membrane-associated guanylate kinases (MAGUKs). Although this suggests that MAGUKs are responsible for the formation of NMDA receptor signaling complexes that enable rapid and selective activation of downstream signaling pathways underlying LTP and LTD, little is known about the specific roles these proteins have in LTP and LTD. In this project we will investigate synaptic transmission and plasticity in mice with mutations in MAGUKs that associate with NMDA receptors (SAP102, PSD-93, and PSD-95) to examine the role of these proteins in LTP and LTD. In addition, we will investigate the role of MAGUKs and other signaling molecules in NMDA receptor-dependent activation of the extracellular signal-regulated kinase pathway, a signaling pathway known to have a key role in LTP and learning. These experiments will provide fundamental insights into the molecular mechanisms underlying activity-dependent forms of synaptic plasticity. Moreover, mutations in the gene for the MAGUK SAP102 have recently been identified as a cause of nonsyndromic X-linked mental retardation. Thus, our studies of synaptic transmission and plasticity in SAP102 mutants will not only provide important insights into the roles of MAGUKs in activity-dependent forms of synaptic plasticity but will also identify potential changes in synaptic function that contribute to learning impairments in this form of metal retardation.